One of the biggest impediments to the successful treatment of cocaine addiction is the high rate of relapse, following even extended periods of drug abstinence. Exposures to stress, drug-paired cues, and cocaine itself have all been shown to increase reports of craving in human drug users and to elicit a reinstatement of drug-seeking behavior in animal models of relapse. However, there is a lacuna in our understanding of the neural circuitry and neuropharmacology via which these stimuli produce their behavioral effects. Without such information, adequate pharmacotherapies for the treatment of cocaine addiction are unlikely. It is the goal of the proposed project to identify the neural circuitry and examine the neurochemistry underlying stress-induced relapse in cocaine self-administration, particularly within the prefrontal cortex, an area important for behavioral responses to stress. In order to accomplish this goal, rats trained to self-administer cocaine will undergo behavioral extinction and then will be tested for their propensity to reinstate drug-taking behavior following exposure to foot shock stress. In some experiments, rats will have one of several target structures reversibly inactivated by GABA agonist treatment prior to reinstatement testing in order to identify the structures that form the requisite circuitry for stress-induced reinstatement. Following identification of the circuit, the relative importance of prefrontal cortex (PFC) glutamate (GLU) afferents to the nucleus accumbens (NA) in stress-induced reinstatement will be assessed by 1) antagonism of NA GLU or dopamine (DA) receptors during reinstatement; or 2) microdialysis for DA and GLU in the NA combined with antagonism of DA, norepinephrine (NE) or corticotropin-releasing factor (CRF) receptors in the PFC. Finally the source of PFC activation will be determined by combining microdialysis for GABA, NE, GLU or DA in the PFC with inactivation techniques. The hypotheses are that 1) limbic structures (including the central extended amygdala and ventral tegmental area) are important for processing stressful stimuli and transmitting information to motor structures (PFC, NA, ventral pallidum) responsible for activating behavioral output; 2) a rise in accumbal GLU mediates behavioral reinstatement; and dopaminergic activation of the PFC from the ventral tegmental afferents is responsible for activating the glutamatergic projection to the NA.